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https://observatorio.fm.usp.br/handle/OPI/31746
Title: | Inhibition of Nuclear PTEN Tyrosine Phosphorylation Enhances Glioma Radiation Sensitivity through Attenuated DNA Repair |
Authors: | MA, Jianhui; BENITE, Jorge A.; LI, Jie; MIKI, Shunichiro; ALBUQUERQU, Claudio Ponte de; GALATRO, Thais; ORELLANA, Laura; ZANCA, Ciro; REED, Rachel; BOYER, Antonia; KOGA, Tomoyuki; VARKI, Nissi M.; FENTON, Tim R.; MARIE, Suely Kazue Nagahashi; LINDAHL, Erik; GAHMAN, Timothy C.; SHIAU, Andrew K.; ZHOU, Huilin; DEGROOT, John; SULMAN, Erik P.; CAVENEE, Webster K.; KOLODNER, Richard D.; CHEN, Clark C.; FURNARI, Frank B. |
Citation: | CANCER CELL, v.35, n.3, p.504-+, 2019 |
Abstract: | Ionizing radiation (IR) and chemotherapy are standard-of-care treatments for glioblastoma (GBM) patients and both result in DNA damage, however, the clinical efficacy is limited due to therapeutic resistance. We identified a mechanism of such resistance mediated by phosphorylation of PTEN on tyrosine 240 (pY240-PTEN) by FGFR2. pY240-PTEN is rapidly elevated and bound to chromatin through interaction with Ki-67 in response to IR treatment and facilitates the recruitment of RAD51 to promote DNA repair. Blocking Y240 phosphorylation confers radiation sensitivity to tumors and extends survival in GBM preclinical models. Y240F-Pten knockin mice showed radiation sensitivity. These results suggest that FGFR-mediated pY240-PTEN is a key mechanism of radiation resistance and is an actionable target for improving radiotherapy efficacy. |
Appears in Collections: | Artigos e Materiais de Revistas Científicas - FM/MNE Artigos e Materiais de Revistas Científicas - LIM/15 Artigos e Materiais de Revistas Científicas - ODS/03 |
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